Van Helsing is able to pick up various weapons, some similar to the ones in the movie to complete the quest. Each weapon, except the elephant gun, has its own ammunition upgrades similar to Capcom's Devil May Cry series in gameplay. An ammo bar indicates how much of the upgraded ammo can be used. Regular ammo is unlimited and use of regular ammo increases the amount of upgraded ammo length. Van Helsing can collect up to three life replenishers, three ammo replenishers and three speed boosts. After every five kills, Van Helsing is able to perform a "finishing move" which will kill the sixth enemy with one hit. Special enemies such as any of the brides, Velkan the werewolf, Dracula or Igor have no response to a finishing move. The list of enemies that Van Helsing encounters during the length of the game include skeletons, flying skulls, small werewolves, skeletons armed with swords, bats, Dracula's children, stone statues, etc. along with the main enemies.

Also, one of the books in a library mentions "the Belmont Family", referencing the Castlevania game series. Another book mentions the murder of Pharaoh Seti I by High Priest Imhotep, a reference to the The Mummy, a film directed by the same director as Van Helsing, Stephen Sommers.